Alnylam Pushes First RNAi Drug That Circulates Through Body Into Human Test

Xconomy Boston — 

Alnylam Pharmaceuticals, one of the leaders in developing drugs through RNA interference, has achieved another big first for the emerging field. The Cambridge, MA-based drug developer (NASDAQ: ALNY) is announcing today that it has filed an application with the FDA to start the first clinical trial of an RNAi drug that can circulate throughout the body.

The drug candidate is built through technology Alnylam licensed from Vancouver, BC-based Tekmira (TSX: TKM). The treatment is designed to deliver two gene-silencing molecules developed by Alnylam via a lipid-nanoparticle capsule from Tekmira. That package (essentially a grease ball) is supposed to protect the drug from breaking down in the bloodstream, making it possible to distribute the gene-silencing molecule throughout the body, and particularly where it needs to be inside liver cancer cells.

This is an important step for the field of RNA interference, says Alnylam CEO John Maraganore. Such drugs have attracted intense interest among pharmaceutical and biotech companies for their potential as a new class of treatments that can shut down disease at its root genetic cause. But one of the biggest challenges is that these gene-silencing drug candidates are broken down and excreted by the kidneys within minutes if given in a straight injection. So researchers have spent years trying to work around this problem, through local delivery for eye diseases, or inhalable forms made for the lungs. By developing a protective lipid-capsule that’s stable, Alnylam hopes this new candidate will blaze a trail for delivering these drugs throughout the body, the same way most effective pills and biotech drugs are delivered.

“This opens the door to a brand new approach to delivering RNAi therapeutics,” Maraganore says. “Systemic delivery is the key enabling event to make this field much more like monoclonal antibodies or small-molecules, in terms of the breadth of diseases we can go after.”

The new candidate, called ALN-VSP, has been designed to treat primary liver tumors and other malignancies that have spread to that organ, Alnylam says. The drug is designed to shut down two critical genes for this type of tumor. The first, kinesin spindle protein, or KSP, is essential for helping tumors spread. The second, vascular endothelial growth factor, or VEGF, is a gene that helps form blood vessels that nourish growing tumors.

Alnylam has run tests in mice that show its drug can suppress the intended genes, shrink tumors, and help the cancerous animals to live longer. ALN-VSP also passed safety tests in rats and non-human primates, Maraganore says.

The drug is designed to be given via a 15-minute intravenous infusion, which could be given once every couple weeks, Maraganore says. The clinical trial is expected to enroll its first patient before the end of June, he says.

This is the first time Alnylam has pursued a cancer drug program. I asked Maraganore why he would pursue liver cancer, in particular, since a relatively new drug, sorafenib (Nexavar) from Onyx Pharmaceuticals and Bayer, has been shown to prolong lives of liver cancer patients, at least partially by blocking the same VEGF target. One big reason is the belief that an RNAi drug can be more effective, because it shuts down the disease earlier in the disease-forming process, rather than after the troublesome proteins get blocked by the competing drug, Maraganore says.

This milestone won’t immediately turn lucrative for Tekmira, but that company will stand to receive an undisclosed milestone payment when Alnylam delivers the first dose of this product to a patient, Maraganore says. The deal between the companies says that Tekmira can get up to $16 million of milestone payments for every product Alnylam develops with its lipid-delivery technology, although most of the payments are tilted toward success in later stages of development, Maraganore says. Tekmira also stands to receive royalty payments if Alnylam can develop any of these drugs into an FDA approved product, he says.